FEBS Lett. 2002 Mar 13;514(2-3):255-9.

The putative effector-binding site of Leishmania mexicana pyruvate kinase studied by site-directed mutagenesis.

Hannaert V, Yernaux C, Rigden DJ, Fothergill-Gilmore LA, Opperdoes FR, Michels PA.

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Research Unit for Tropical Diseases, Christian de Duve Institute of Cellular Pathology and Laboratory of Biochemistry, Université Catholique de Louvain, ICP-TROP 74.39 Avenue Hippocrate, B-1200 Brussels, Belgium. hannaert@trop.ucl.ac.be

Abstract

The activity of pyruvate kinase of Leishmania mexicana is allosterically regulated by fructose 2,6-bisphosphate (F-2,6-P(2)), contrary to the pyruvate kinases from other eukaryotes that are usually stimulated by fructose 1,6-bisphosphate (F-1,6-P(2)). Based on the comparison of the three-dimensional structure of Saccharomyces cerevisiae pyruvate kinase crystallized with F-1,6-P(2) present at the effector site (R-state) and the L. mexicana enzyme crystallized in the T-state, two residues (Lys453 and His480) were proposed to bind the 2-phospho group of the effector. This hypothesis was tested by site-directed mutagenesis. The allosteric activation by F-2,6-P(2) appeared to be entirely abrogated in the mutated enzymes confirming our predictions.

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